1. Use of Drug Eluting Stents for In-Stent Restenosis: Are We There Yet? Jose Diez, M.D. Robert Smith, M.D. Cardiac Catheterization Conference March 23, 2004

2. Outline Case presentation with LHC results Traditional approaches for dealing with in-stent restenosis –Cutting Balloon Angioplasty (CBA) –Brachytherapy –PTCA –Bare Metal Stent Drug eluting stents for in-stent restenosis Conclusions

3. Case Presentation JD is a 72 yo AAF with h/o CAD s/p stenting to RCA and LAD in 10/03 who was referred for elective LHC after describing a history of progressive SOB and chest pain. She described the chest pain as precordial, pressure like, and similar to previous episodes of angina. Her chest pain was typically less than a few minutes, relieved with SL NTG, and occurred sometimes with exertion and sometimes at rest. It was usually associated with SOB. She first experienced the chest pain approximately 2 months after stent placement (12/03) and underwent a negative stress echo at that time. In 2/04, she was evaluated and discharged from the ER for similar episodes of chest pain with SOB. Subsequently, an adenosine cardiolyte stress test was negative for ischemia. Because of persistence of her symptoms, she was referred for LHC.

4. Past Medical History CAD s/p STEMI in 10/03 with stent to culprit RCA lesion (Medtronic Zipper) and stent to LAD (Cypher) Exercise stress echo 12/03 negative for ischemia. Pt exercised for 7 minutes Adenosine cardiolyte stress test 2/04 negative for ischemia TTE 2000 showed moderate AI, concentric LVH, mild MR HTN for > 10 years Type II DM on oral hypoglycemics Hyperlipidemia PVD Cerebrovascular disease s/p left CEA and 60% lesion in the right internal CA (h/o TIA’s) Obstructive Sleep Apnea on home CPAP

5. Medications Plavix 75mg PO QD ASA 81mg PO QD Lopressor 50mg PO BID Lisinopril 40mg PO QD Atorvastatin 80mg PO QHS

6. Social History Retired Nurse Denies h/o cigarette smoking Denies EtOH Denies drug use Lives with daughter Husband is deceased

7. Family History Father died of “congestive heart failure” Also significant for DM, HTN

8. Physical Exam 152/88 52 14 36.0 SaO2 97% Gen: NAD, symptom free Neck: Right Carotid Bruit, No JVD CV: nlS1S2, 2/6 HSM apex  axilla Chest: clear Abd: NABS, NT, ND Ext: no edema

9. Labs Na 133 K 4.1 Cl 101 CO 2 29 Glu 172 BUN 11 Cr 0.6 Ca 1.8 Mg 1.8 Tn <0.04 Myo 22 CK 68 WBC 6.6 Hgb 12.5 Hct 36.5 MCV 87.5 Plt 221 PTT 26 INR 1.02

10. ECG NSR with q waves in the inferior leads

11. Restenosis Occurs in 30-40% of patients by 6 months after PTCA Occurs in 20-30% of patients by 6 months after PTCA with stenting 1,2 Restenosis is thought secondary to combination of vessel wall remodeling and neointimal hyperplasia with smooth muscle cell and matrix proliferation Elastic recoil and thrombosis may also play a role 1 Fischman et al., N Engl J Med 1994;331:496-501 2 Serruys et al., N Engl J Med 1994;331:489-495

12. ISR; Available Therapies Cutting Balloon Angioplasty (CBA) Angioplasty Brachytherapy Stent within Stent –Bare Metal Stents –Drug Eluting Stents

13. Cutting Balloon Angioplasty The cutting balloon is a device with 3-4 longitudinal atherotome blades mounted on the outer surface of the device It produces longitudinal incisions in a target lesion resulting in more effective dilatation of the lesion Keeps the balloon from moving proximally or distally during inflation May help facilitate extrusion of in-stent hyperplasia through the stent struts

14. Cutting Balloon

15. Cutting Balloon Angioplasty for ISR In a 2001 study, CBA was compared to rotational atherectomy, PTCA, or restenting in a study of 684 patients with ISR 1 At angiographic f/u, CBA was associated with less lumen loss than that seen with atherectomy and stent This corresponded to a 6 month restenosis rate of 20% for CBA, 36% for atherectomy, and 41% for restenting At 11 month follow up, there was no difference in the incidence death, MI, or bypass surgery 1 Adamian et al. J Am Coll Cardiol 2001 Sep;38(3):672-9

16. Brachytherapy for ISR Intracoronary brachytherapy reduces vessel wall remodeling and causes a reduction in the proliferation of the neointima The SCRIPPS Trial 1 was a double blind randomized trial that compared gamma irradiation to placebo for treatment of ISR (n=55). Follow up was performed at 6 months, 3 years, and 5 years 23% of patients had recurrent stenosis at angiographic follow up 1 Grise et al., Circulation. 105(23):2737-2740, June 11, 2002

17. SCRIPPS Trial: 5 Year F/U

18. SCRIPPS Trial: TLR

19. SCRIPPS Trial: Event Free Survival

20. PTCA for ISR In a 1998 study, PTCA was performed in 52 patients presenting with ISR 1 Initial angiographic success rate was 100% At 6 month follow up, angiographic restenosis rate was 54% 18 patients (35%) had TVR No patients died Conclusions: PTCA for ISR is safe but has a high rate of recurrent stenosis 1 Eltchaninoff et al., J Am Coll Cardiol 1998 Oct;32(4): 980-984

21. Repeat Stenting for ISR In a study from 2000, 65 patients underwent repeat stenting as treatment for ISR 1 Angiographic success was obtained in all patients 3 patients had acute adverse events (1 death, 2 NQWMI’s) During follow up (17+/- 11 months), TVR was required in 14% Angiographic follow up (mean of 9 months) showed ISR in 30% 1 Alfonso et al., Am J Cardiol 2000 Feb 1;85(3):327-32

22. Repeat Stenting vs. PTCA Addressed in the RIBS trial 1 (compared repeat stenting to PTCA alone in 450 patients) Restenosis rate and event free survival at 6 months were similar in the two groups Among patients with a target vessel diameter > or equal to 3mm, stenting was associated with a significantly lower restenosis rate (27% vs. 49% for PTCA) at 6 months 1 Alfonso et al., J Am Coll Cardiol 2003 Sep 3;42(5):796-805

23. Repeat Stenting vs. PTCA In vessels > or equal to 3mm, patients who were restented had better event free one year survival (84% vs. 62%) There was an almost significant trend toward worse outcomes with re-stenting when the vessel diameter was less than 3mm

24. Summary of Restenosis Rates Brachytherapy: 12% at 6 months and 23% at 5 years CBA: 20% at 6 months PTCA: 54% at 6 months, 49% at 6 months Bare Metal Stents: 41% at 6 months, 30% at 9 months, 27% at 6 months

25. Drug Eluting Stents for ISR The efficacy of Sirolimus Eluting Stents has been evaluated in 2 small, noncomparative trials 1,2 The efficacy of Paclitaxel eluting stents has also been evaluated in a single noncomparative trial 3 1 Degertekin et al., J Am Coll Cardiol 2003 Jan 15;41(2):184-9 2 Sousa et al., Circulation 2003; 107:24 3 Tanabe et al., Circulation 2003 Feb 4;107(4): 559-564

26. Drug Eluting Stents for ISR In an initial series of 25 patients with ISR in whom a SES was implanted, all vessels were patent at 1 year and only one patient developed ISR within the newer stent 1 Exclusion criteria for this study included lesions in SVG’s, patients who had undergone previous brachytherapy to the target vessel, and lesions greater than 36mm in length No ostial lesions were treated in this study 1 Sousa et al., Circulation 2003; 107:24

27. Drug Eluting Stents for ISR Post procedure angiography and IVUS was performed at 4 and 12 months All patients were free of angina after 1 year There were no repeat revascularizations, stent thromboses, or major clinical events (CVA, MI, Death) after 1 year On 4 month angiographic follow up, lumen diameter was unchanged in 50% of patients, and slightly greater in some patients

28. Drug Eluting Stents for ISR There was a slight but significant decrease in mean lumen diameter between 4 and 12 months (angiographic late loss averaged 0.07mm at 4 months and 0.36mm at 12 months) Volume obstruction by IVUS was 0.81% at 4 months and 1.76% at 12 months No patients had ISR at 4 months and 1 patient had ISR at 1 year All stents were properly deployed

30. Drug Eluting Stents for ISR In a second report 1, 16 patients with severe, recurrent ISR in a native coronary vessel received a SES (average lesion length 18.4mm) Patients with objective evidence of ischemia were excluded 4 patients has total occlusions pre-procedure and 3 others had received brachytherapy Quantitative angiographic and IVUS follow up was performed at 4 months and clinical follow up at 9 months 1 Degertekin et al., J Am Coll Cardiol 2003 Jan 15;41(2):184-9

31. Drug Eluting Stents for ISR At 4 month follow up, one patient had died and three patients had angiographic evidence of restenosis (18.8%) Late lumen loss averaged 0.21mm and volume obstruction of the stent by IVUS was 1.1% At 9 months clinical follow up, 3 patients had experienced major adverse events (2 deaths and 1 MI)

33. Drug Eluting Stents for ISR The TAXUS III Trial 1 evaluated paclitaxel eluting stents for treatment of ISR This was a noncomparative 2 center study that evaluated 28 patients with ISR Inclusion criteria were lesions < or = to 30mm, 50-99% stenosis, and vessel diameter 3.0 to 3.5mm Exclusion criteria were AMI, LVEF 1.7, and contraindication to antiplatelet therapy 1 Tanabe et al., Circulation 2003 Feb 4;107(4): 559-564

34. Drug Eluting Stents for ISR There was no subacute stent thrombosis 25 of 28 patients completed angiographic follow up at 6 months 4 patients had angiographic evidence of restenosis (16%) One of these patients had total occlusion of a lesion previously treated with a gold coated stent (he was asymptomatic) One patient had ISR in a bare metal stent used to treat a dissection at the end of a PES Two patients has ISR in gaps between sequential PES’s The mean lumen late loss was 0.54mm

36. Drug Eluting Stents for ISR The major adverse cardiac event rate was 29% (8 patients) This included 1 NQWMI, 1 CABG, and 5 TLR’s 1 patient with ISR of bare metal stent and 2 patients with stenoses of gaps between PES’s 2 patients without angiographic restenosis underwent TLR as result of IVUS assessment at follow up (1 incomplete apposition and 1 insufficient expansion of the stent

37. Conclusions Treating ISR is a major challenge facing interventional cardiologists With traditional treatments (PTCA, CBA, re- stenting), restenosis develops in 30-80% of patients Prior to drug eluting stents, the best therapy was intravascular brachytherapy (23% restenosis in the SCRIPPS trial) Early studies indicate that drug eluting stents may prove effective for treating in-stent restenosis

38. Conclusions Between all DES studies, there was no subacute thrombosis Between all studies, there were only 4 compelling cases of ISR within a DES When the DES’s were properly deployed, there were only 6 adverse cardiac events between the studies Sirolimus eluting stents and paclitaxel eluting stents both appear to be effective for treating ISR Early data indicates that DES’s are superior than traditional methods for treating ISR Are we there yet? Maybe…